In the post-HAART era, patients continue to suffer from the adverse medical consequences of HIV/AIDS. The adverse effects include incomplete immune reconstitution, chronic inflammation, depression, increased risk of cardiovascular and metabolic disease, and low bone density. Clinical trials suggest that vitamin D supplements can increase bone density, reduce inflammation, alleviate depression, and increase longevity if given in adequate doses. To achieve maximum benefits, most vitamin D experts agree that vitamin D treatments should raise the concentration of 25-hydroxyvitamin D [25(OH)D] above 30 ng/ml. A growing number of HIV care providers desire an evidence-based protocol for achieving these 25(OH)D target levels. This project addresses the need for a validated protocol for treating vitamin D deficiency in HIV- positive individuals on HAART. The goal of Aim I is to conduct a 12-mo randomized, double- blinded trial comparing two dosing regimens of oral vitamin D plus 0.5 g/d of calcium in patients on stable HAART who have 25(OH)D levels 25 ng/ml and undetectable HIV viral load at baseline (100 per arm). Medication event monitoring system (MEMS) caps will be used to record supplement use and to promote adherence. Subjects in Protocol A will receive 50,000 IU/wk of vitamin D2 for 8 wk followed by 1000 IU/d of vitamin D3 for 48 wk. Subjects in Protocol B will receive 2000-4000 IU/d of vitamin D3, depending on the basal 25(OH)D level, with dose titration, as necessary, based on the slope of the initial response. The primary outcome measure is the difference in the percentage of subjects with 25(OH)D levels in the range of 30- 60 ng/ml at 12 mo. The secondary outcome is the slope of the 25(OH)D response curve during various time intervals. The goal of Aim II is to compare the impact of the two protocols on markers of disease. The primary outcome measure is the change in the CD4+T cell count. Secondary outcomes include changes in CD4+ T cell subsets, markers of inflammation, markers of bone and calcium metabolism, self-reported psychological status, viral load, side effects, safety, and adherence. To our knowledge, this trial is the first head-to-head comparison of a regimen that uses a loading dose of vitamin D2 with a regimen that uses a tiered starting dose of vitamin D3. The project will yield a validated protocol for treating vitamin D deficiency in HIV- infected patients on HAART and will provide initial data about the risks and health benefits of vitamin D and calcium supplements. This information is essential for designing definitive multicenter trials in the future. PUBLIC HEALTH RELEVANCE: The ability of vitamin D to modulate the immune system and strengthen bones may mitigate the adverse medi- cation consequences of HIV/AIDS, but little is known about either the health benefits of vitamin D supplements, or about the optimal dosing regimen for patients on highly active antiretroviral therapy (HAART). Our trial is a comparison of two regimens for administering vitamin D and calcium to HIV-positive individuals taking antiviral medications. Our study will help physicians make evidence-based decisions about the most effective way to use vitamin D in their patients and enable the design of large multi-center trials in the future.